Discovery and biological profile of isoindolinone derivatives as novel metabotropic glutamate receptor 1 antagonists: A potential treatment for psychotic disorders

Discovery and in vitro and in vivo profiles of N-ethyl-N-[2-[3-(5-fluoro-2-pyridinyl)-1H-pyrazol-1-yl]ethyl]-2-(2H-1,2,3-triazol-2-yl)-benzamide as a novel class of dual orexin receptor antagonist

“…Various kinds of Ar replacements were then introduced with the exception of 2-and 4-fluoropyridine derivatives, since these analogues have a possibility of drug-protein covalent binding because of the potential electrophilicity of such fluoropyridine structures. 18 Among them, 2-trifluoromethyl-6-pyridine (4d), 6-methyl-2-pyridine (4e), and 4-fluorobenzene (4f) analogues showed almost the same antagonistic potency as that of 4a. Unfortunately, these analogues had relatively high lipophilic natures.…”

“…The resulting residue was purified by column chromatography (5-50% EtOAc in hexanes) to give the title compound 18 as a pale yellow powder (0.12 g, 18% over 2 steps). HRMS calcd for C 18 (19) Hydrazine monohydrate (0.035 mL, 0.71 mmol) was dropwise added to a solution of 2-{2-[3-(5-fluoropyridin-2-yl)-1,2-oxazol-5-yl]ethyl}-1H-isoindole-1,3(2H)-dione (0.12 g, 0.36 mmol) in EtOH (5 mL), followed by stirring at 90°C for 2 h. After cooling at room temperature, the precipitated solid was removed by filtration. The filtrate was concentrated under reduced pressure.…”

Synthesis and biological evaluation of aryl isoxazole derivatives as metabotropic glutamate receptor 1 antagonists: A potential treatment for neuropathic pain

“…Compound 1 demonstrated an excellent pharmacokinetic profile and an antipsychotic-like effect in an animal model without any noticeable toxicity, however, its analgesic activity was never tested in vivo. 20 On the basis of these findings, we decided to modify the triazole scaffold in compound 1 to an aryl isoxazole scaffold in hopes to develop selective mGluR1 antagonists with an antinociceptive activity. Herein, we report the synthesis and biological evaluation of novel aryl isoxazole derivatives as selective mGluR1 antagonists for the treatment of neuropathic pain.…”

“…[12][13][14] To develop selective modulators of mGluR1, much interest has focused on allosteric sites, due to the highly conserved nature of the glutamate binding sites of mGluRs. 19 and triazole 20,21 derivatives. Notably, Merck-Banyu laboratory developed a highly selective and potent antagonist, as depicted as compound 1 in Figure 1.…”

Regioselective Synthesis of the 5,6‐Dihydro‐4H‐furo[2,3‐c]pyrrol‐4‐one Skeleton: A New Class of Compounds

“…A series of isoindolinone derivatives have recently been synthesized and screened. Some substituted isoindolinone derivatives have quite potent metabotropic glutamate receptor 1 antagonist activity [1]. Moreover, it has been demonstrated that some derivatives show an antipsychotic-like effect in an animal model.…”